Nuclear magnetic resonance, hereinafter NMR, is relatively a recent method in radiology with respect to the study and imaging of intact biological systems. Like X-rays and ultrasound procedures, NMR is a non-invasive analytical technique employed as a means to examine a body. Unlike X-rays, however, NMR is a non-ionizing, non-destructive process that can be employed continuously to a host. Further, NMR imaging is capable of providing anatomical information comparable to that supplied by X-ray CAT scans. In comparison to ultrasound, the quality of projections or images reconstructed from currently known NMR techniques either rival or transcend those observed with ultrasound procedures. Thus, these rather unusual and highly desirable characteristics provide NMR with present potential to be one of the most versatile and useful diagnosing tools ever used in biological and medical communities today.
Basically, NMR is a process that results when nuclei with magnetic moments are subjected to a magnetic field. If electromagnetic radiation in the radio-frequency region of the spectrum is subsequently applied, the magnetized nuclei will emit a detectable signal having a frequency similar to the one applied.
More specifically, NMR predicates on the fact that many nuclei have an intrinsic magnetism resulting from an angular momentum, or spin, of such nuclei. Resembling a bar magnet, the spin property generates a magnetic dipole, or magnetic moment, around such nuclei. Thus, when two external fields are applied to an object, the strong magnetic field causes the dipoles for such nuclei, e.g., nuclei with spin designated 1/2, to align either parallel or anti-parallel with said magnetic field. Of the two orientations, the parallel alignment requires the nuclei to store less energy and hence is the stable or preferred orientation. As to the second applied field, comprising radio-frequency waves of a precise frequency or quantum of electromagnetic radiation, it will cause such nuclei to nutate or flip into the less stable orientation. In an attempt to re-establish the preferred parallel or stable orientation, the excited nuclei will emit electromagnetic radio waves at a frequency nominally proportional to the magnitude of the strong field, but specifically characteristic of their chemical environment.
Thus, the NMR technique detects radio-frequency signals emitted from nuclei as a result of a process undergone by such nuclei when exposed to at least two externally applied fields. If a third magnetic field in the form of a gradient is applied, nuclei with the same magnetogyric constant will nutate at different frequencies, i.e., Larmor frequencies, depending upon the location within the object. Thus, similar nuclei in an object can be detected discriminately for a particular region in said object according to their Larmor frequency corresponding to a particular magnetic field strength along the applied magnetic gradient, as demonstrated by the following equation f.sub.o =(.gamma.)H.sub.o wherein f.sub.o is the Larmor frequency, .gamma. is the magnetogyric constant, and H.sub.o is the applied magnetic field.
Unfortunately, there are several factors that may limit the usefulness of NMR applications in vivo. In general, NMR is an insensitive radiologic modality requiring significant amounts of nuclei with magnetic moments to be present in an object. Consequently, not all nuclei in vivo are present in sufficient quantities to be detected by present NMR techniques. Further, not all nuclei in vivo have magnetic moments. Some of the more common isotopes that do not have magnetic moments which are found in vivo include carbon-12, oxygen-16 and sulfur-32. Thus, current NMR applications in vivo are restricted to those nuclei that have magnetic moments and are sufficiently abundant to overcome the insensitivity of present NMR techniques.
Heretofore, NMR applications in vivo have almost invariably been concerned with imaging or detecting the water distribution within a region of interest derived from the detection of proton resonance. Other nuclei not only have lower intrinsic NMR sensitivities, but also are less abundant in biological material. Consideration has, however, been given to the use of other nuclei such as phosphorus-31 which represents the next best choice for NMR in vivo applications due to its natural and abundant occurrence in biological fluids. For example, phosphorus-31 NMR has been found to provide an indirect means for determining intracellular pH and Mg.sup.++ concentration simply by measuring the chemical shift of the inorganic phosphate resonance in vivo and determining from a standard titration curve the pH or Mg.sup.++ concentration to which the chemical shift corresponds. The type of information available from NMR. IN: Gadian, D.G.: Nuclear Magnetic Resonance and Its Applications to Living Systems. First Edition. Oxford: Clarendon Press. pp. 23-42 (1982); Moon, R. B. and Richards, J. H.: Determination of Intracellular pH By .sup.31 P Magnetic Resonance. J. Biological Chemistry. 218(20):7276-7278 (Oct. 25, 1973). In addition, sodium-23 has been used to image a heart perfused with a medium containing 145 mM sodium in vivo. Unfortunately, difficulties with these nuclei arise because of the inherent sensitivity losses due to the lower resonant frequencies of these nuclei. Moon, R. B. and Richards, J. H.: Determination of Intracellular pH By .sup.31 P Magnetic Resonance. J. Biological Chemistry. 218(20):7276-7278 (Oct. 25, 1973).
Another stable element which is uniquely suited for NMR imaging is fluorine because its intrinsic sensitivity practically commensurates with that of protons, it has a spin of 1/2, so as to give relatively uncomplicated, well-resolved spectra, its natural isotopic abundance is 100 percent, it gives large chemical shifts, and because its magnetogyric constant is similar to that of protons, the same equipment can be used. Unfortunately, fluorine NMR applications in vivo are in effect not conducted due to the practical non-existence in biological materials of fluorine observable by NMR methods normally employed in studying biological systems. However, nuclear medicine procedures using the positron emitter fluorine-18 are well documented and include, for example, bone scanning, brain metabolism and infarct investigations using fluorodeoxyglucose, and myocardial blood flow and metabolism. With respect to fluorine NMR imaging, some investigations into such applications have been made. Suggestions have been presented involving the study of vascular system disorders, in conjunction with fluorocarbon blood substitutes, Holland, G. N. et al: .sup.19 F Magnetic Resonance Imaging. J. Magnetic Resonance. 28:133-136 (1977), and the localization/kinetics of fluorocarbon following liquid breathing. Further, in vitro canine studies investigating the feasibility of fluorine as an agent for NMR imaging of myocardial infarction have also been performed. The above cited principles and studies directed to flourine are acknowledged in Thomas, S. R. et al: Nuclear Magnetic Resonance Imaging Techniques Developed Modestly Within a University Medical Center Environment: What Can the Small System Contribute at this Point? Magnetic Resonance Imaging. 1(1):11-21 (1981). Further, an NMR technique in an object other than an animal has been described for the determination of magnetic susceptibilities of oxygen in benzene or hexafluorobenzene solutions in order to estimate the amount of dissolved oxygen therein. For example, this method might be used for a remote control of oxygen content in organic solvents for oxygen pressures higher than one atmosphere. Delpuech, J. J., Hanza, M. A., and Serratrice, G.: Determination of Oxygen By a Nuclear Magnetic Resonance Method. J. Magnetic Resonance. 36:173-179 (1979). Finally, it has been demonstrated with NMR techniques in an object other than an animal that the solubilities of oxygen (in mole fractions) are higher in fluoroalkanes than in previously reported hexafluorobenzene. Hanza, M. A. et al.: Fluorocarbons as Oxygen Carriers. II. An NMR Study of Partially or Totally Fluorinated Alkanes and Alkenes. J. Magnetic Resonance. 42:227-241 (1981).
Studies directed to conformational equilibria and equilibration by NMR spectroscopy have been conducted, particularly with cyclohexane and fluorocyclohexane rings. In such applications, the position of the equilibria between conformational isomers and measurements of rates of equilibration of such isomers as a function of temperature have been determined. The studies, however, were dependent upon the implementation of known temperatures to determine the equilibria and equilibrium rates. Roberts. J. D.: Studies of Conformational Equilibria and Equilibration by Nuclear Magnetic Resonance Spectroscopy. Chemistry in Britain. 2:529-535 (1966); Homer, J. and Thomas, L. F.: Nuclear Magnetic Resonance Spectra of Cyclic Fluorocarbons. Trans. Faraday Soc. 59:2431-2443 (1963). Further, it has been illustrated that carbon-13 may be employed as a kinetic thermometer in a laboratory environment. This particular application requires the examination system to contain at least two chemically exchanging sites which correspond to one exchange process and an independent means of determining the kinetic parameters describing the exchange process in order for carbon-13 to serve as a kinetic thermometer. Such application, however, is limited to determining temperature at coalescence and, thus, is operable at only one temperature for each independent exchange process as opposed to over a continous range. Further, the method is employed as a calibration technique. Still further, its accuracy is inherently unreliable to be of practical significance. Sternhell, S.: Kinetic .sup.13 C NMR Thermometer. Texas A&M University NMR Newsletter. No. 285: 21-23 (June 1982).
Temperature has been measured by means of the NMR spectrum of a liquid sample for the purpose of calibrating the temperature control apparatus of an NMR spectrometer. Many features of the NMR spectrum, for instance chemical shifts, often show weak temperature dependence, and could be used to determine temperature. Bornais, Jr. and Brownstein, S.: A Low-Temperature Thermometer for .sup.1 H, .sup.19 F, and .sup.13 C. J. Magnetic Resonance. 29:207-211 (1978). In this particular reference, the peak separation and spin-spin coupling in the proton NMR spectrum of a liquid test sample changed by 1.75 Hz and 0.07 Hz, respectively, when the temperature was varied by 20.5.degree. C. In objects, such as animals, where the best obtainable spectral resolution could be 10 to 50 Hz or larger, and it is desired to measure temperatures to an accuracy of 1.degree. C. or 2.degree. C. or better, such a means of temperature measurement is inapplicable.
As to temperature in an animal, it is well known that temperature provides clinicians with an excellent prognostic indicator as to the condition of the animal. For instance, an abnormal fluctuation in temperature such as an increase may reflect infection or hyperthermia, while a decrease may represent ischemia or hypothermia. Thus, it is necessary to measure temperature in an animal accurately, inexpensively and reliably. Heretofore, temperature measurements have generally consisted of invasive and cumbersome techniques that often result in less than reliable measurements. For example, present techniques comprise invading needles, electrical wires, cables, or instruments that must be inserted into a region of interest. Such penetrating procedures possess unfortunately the potential to cause chemical and biological contamination to the host. Thus, proper preparation and sterilization procedures are required to prevent transmittal and corrosive contamination should the instruments to detect temperature be reused. Another disadvantage inherent to the conventional techniques concerns the discomfort and inconvenience experienced from communication with penetrating probes. Consequently, the accuracy and reliability of these conventional techniques may be adversely compromised. As to highly delicate structures, the temperature may be obtained but not without sacrifice to the integrity of the structure. Generally, the structure may be damaged, repositioned, or its dimensions changed. There is a further possibility of short circuiting the employed instruments adding additional expense and time to the procedure. Still another disadvantage involves the susceptibility of the instrument itself when exposed to physical and chemical extremes which may interfere with its reliability. Finally, conventional techniques are unable to measure a continuous temperature field in an object or animal and, thus, the invasive and cumbersome procedure must be duplicated for each time or at each point in space a temperature measurement is desired, or employ simultaneously a large number of temperature sensors.
It is apparent from the above brief overview directed to the limitations of NMR techniques and various methods for measuring temperature in an object or animal and the current state of knowledge that there is a need to provide an improved method that more effectively and advantageously detects, measures, and monitors continuously temperatures of an object or animal.